The HIV-1 external glycoprotein, gp120, has been implicated in the development of AIDS dementia complex. The goal of this project is to investigate the neurotoxicity of this molecule, as summarized in two specific aims: 1) Is gp120 toxic to neurons in vivo? 2) Is the secreted form of gp120 neurotoxic in vitro and, if so, does neurotoxicity vary with the HIV strain of origin? The hypothesis that gp120 is neurotoxic in vivo will be tested using transgenic mice that secrete gp120 from one of the following central nervous system (CNS) cells: 1) all neurons; 2) oligodendrocytes; 3) cerebellar Purkinje cells. tissue-specific promoters will be used to expose neurons to gp120 arising from several distinct cellular sources in vivo. These studies will also test whether the effect of gp120 secretion is independent of its site of production. gp120-producing transgenic mice will be systematically analyzed for neuropathological alterations similar to those of ADC. In parallel to the transgenic experiments, gp120-induced neurotoxicity will be determined in primary neuronal cultures allowing direct testing of the hypothesis that gp120-induced neurotoxicity in vitro accurately reflects gp120 actions in vivo. The possibility will be explored that neurotoxicity varies with differences in sequence and cell tropism by using gp120 subunits from different isolates. The subunits of macrophage-tropic and lymphotropic isolates will be expressed in cultured cell lines using recombinant expression vectors. Cells will be co-cultured with primary neuronal cells and the viability of the neurons assessed. In addition, the culture medium of the infected cells will be used as the source of gp120 for the neurotoxicity studies in vitro. The studies proposed in this application are aimed at understanding the role of the HIV-1 envelope glycoprotein in the AIDS dementia complex. The information obtained from these experiments may provide an important model of retrovirus-induced neurodegeneration and contribute to the development of improved therapeutic modalities for this AIDS complication.